Alzheimer's disease (AD) can be viewed as a chronic degenerative and inflammatory disease leading to neuronal dysfunction and loss that are critically linked to accumulation of fibrillogenic fragments (Abeta[1-42/43]) of beta-amyloid precursor protein (APP). One leading possibility to explain how Abeta accumulation leads to neurotoxicity is that Abeta triggers oxidative and/or nitrosative injury. Fibrillogenic Abeta can generate oxidants in vitro and can elicit production of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) from microglia, astrocytes, neurons and monocytes in vitro (alone or with cytokines) and when injected into the brain. Biochemical and histochemical hallmarks of oxidative/nitrosative injury have been documented in lesions of AD. Among these, expression of the inducible isoform of nitric oxide synthase (NOS2; iNOS) is of special interest because its presence in brain is abnormal and implies inflammation; its production of NO is usually more sustained and destructive than that of other NOS's; it can produce ROI simultaneously with RNI, both by its own enzymatic action and by damaging mitochondria; and the resulting production of NO and superoxide in the same time and place favors the formation of peroxynitrite. Peroxynitrite is more toxic than either of its precursors, and there is strong histochemical evidence for its formation in AD. The PI has collaborated in demonstrating the presence of NOS2 in brains of patients with AD, associated with tangle-bearing neurons and neuropil. The advent of mice bearing AD-associated transgenes and the PI's generation of mice with disrupted alleles for NOS2 now permit a genetic test of the hypothesis that NOS2 may be an important enzymatic contributor to the oxidative/nitrosative neuronal injury characteristic of AD. Preliminary studies in 4 transgenic mouse models of AD using well-characterized antibodies for NOS2 have demonstrated NOS2 immunoreactivity in each type of AD-prone mouse. In contrast, cyclooxygenase 2 was scarcely detectable. In this proposal, mice carrying two AD-associated transgenes will be bred to retain or lose functional alleles of NOS2. These two strains will be compared with each other and with littermate- derived wild type mice as a function of age. If inability to express NOS2 decreases, delays, slows, or reduces the incidence, onset, progression or severity of neuronal loss or oxidative injury in mice with AD-associated transgenes, then NOS2 will emerge as an important target for experimental therapy in AD.